{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:47:10Z","timestamp":1785415630702,"version":"3.56.0"},"reference-count":42,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011912","name":"Taipei Veterans General Hospital","doi-asserted-by":"publisher","award":["V110B-007"],"award-info":[{"award-number":["V110B-007"]}],"id":[{"id":"10.13039\/501100011912","id-type":"DOI","asserted-by":"publisher"}]},{"award":["V110B-007"],"award-info":[{"award-number":["V110B-007"]}],"id":[{"id":"https:\/\/ror.org\/03ymy8z76","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Background\/Objectives: Whole exome sequencing (WES) has emerged as a clinically valuable second-tier test following abnormal biochemical newborn screening (NBS). However, population-specific data on diagnostic yield, secondary findings (SFs), and exome-wide carrier burden remain scarce in East Asian neonates, particularly since the release of the ACMG SF v3.3 gene list. We aimed to characterize these metrics in a Taiwanese neonatal cohort. Methods: We retrospectively analyzed 118 consecutive neonates referred to Taipei Veterans General Hospital between August 2021 and August 2022 following abnormal biochemical NBS. WES was performed on the Illumina NovaSeq 6000 platform; variants were classified per the 2015 ACMG\/AMP framework and re-evaluated under ACMG SF v3.3. Referral categories comprised lysosomal storage diseases (n = 61), amino acid disorders (n = 38), fatty acid oxidation disorders (n = 13), and organic acid disorders (n = 6). Results: Fifty neonates (42.4%) received confirmed molecular diagnoses and 45 (38.1%) were carriers (combined molecular resolution 80.5%). Five participants (4.2%) harbored pathogenic\/likely pathogenic variants in ACMG SF v3.3 genes (TTN, LDLR, PTEN, RYR1, TP53). Incidental findings occurred in 51.7%, and at least one recessive-carrier variant was detected in 99.2% (mean 4.15 per individual; median 4). The Taiwanese-specific c.639+919G&gt;A cardiac Fabry variant accounted for 24\/25 confirmed male Fabry cases, and the p.Gly576Ser pseudodeficiency allele confounded all suspected Pompe cases. Conclusions: Second-tier WES substantially improves diagnostic precision, discriminating confirmed diagnoses from carrier, pseudodeficiency, and biochemical false-positive states. The high carrier burden and incidental-finding rate underscore the importance of comprehensive pre- and post-test genetic counseling in East Asian neonatal genomic programs.<\/jats:p>","DOI":"10.3390\/children13080977","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T09:11:26Z","timestamp":1784797886000},"page":"977","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Second-Tier Whole Exome Sequencing Following Abnormal Newborn Screening: Diagnostic Yield, Secondary Findings, and Carrier Burden in a Taiwanese Neonatal Cohort"],"prefix":"10.3390","volume":"13","author":[{"given":"Cheng-Yu","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Taipei Veterans General Hospital, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3962-1739","authenticated-orcid":false,"given":"Dau-Ming","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Taipei Veterans General Hospital, Taipei 112, Taiwan"},{"name":"Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Feng","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Taipei Veterans General Hospital, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5175-4772","authenticated-orcid":false,"given":"Yann-Jang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Taipei Veterans General Hospital, Taipei 112, Taiwan"},{"name":"Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"},{"name":"Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"},{"name":"Department of Education and Research, Taipei City Hospital, Taipei 106, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.pcl.2025.04.005","article-title":"Advances in Newborn Screening","volume":"72","author":"Powell","year":"2025","journal-title":"Pediatr. 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